Authors:	El Hamdaoui, Yamina Zheng, Fang Fritz, Nikolas Ye, Lian Tran, Mai Anh Schwickert, Kevin Schirmeister, Tanja Braeuning, Albert Lichtenstein, Dajana Hellmich, Ute A. Weikert, Dorothee Heinrich, Markus Treccani, Giulia Schäfer, Michael K. E. Nowak, Gabriel Nürnberg, Bernd Alzheimer, Christian Müller, Christian P. Friedland, Kristina
Title:	Analysis of hyperforin (St. John’s wort) action at TRPC6 channel leads to the development of a new class of antidepressant drugs
Online publication date:	18-Jan-2023
Year of first publication:	2022
Language:	english
Abstract:	St. John’s wort is an herb, long used in folk medicine for the treatment of mild depression. Its antidepressant constituent, hyperforin, has properties such as chemical instability and induction of drug-drug interactions that preclude its use for individual pharmacotherapies. Here we identify the transient receptor potential canonical 6 channel (TRPC6) as a druggable target to control anxious and depressive behavior and as a requirement for hyperforin antidepressant action. We demonstrate that TRPC6 deficiency in mice not only results in anxious and depressive behavior, but also reduces excitability of hippocampal CA1 pyramidal neurons and dentate gyrus granule cells. Using electrophysiology and targeted mutagenesis, we show that hyperforin activates the channel via a specific binding motif at TRPC6. We performed an analysis of hyperforin action to develop a new antidepressant drug that uses the same TRPC6 target mechanism for its antidepressant action. We synthesized the hyperforin analog Hyp13, which shows similar binding to TRPC6 and recapitulates TRPC6-dependent anxiolytic and antidepressant effects in mice. Hyp13 does not activate pregnan-X-receptor (PXR) and thereby loses the potential to induce drug-drug interactions. This may provide a new approach to develop better treatments for depression, since depression remains one of the most treatment-resistant mental disorders, warranting the development of effective drugs based on naturally occurring compounds.
DDC:	610 Medizin 610 Medical sciences
Institution:	Johannes Gutenberg-Universität Mainz
Department:	FB 09 Chemie, Pharmazie u. Geowissensch. FB 04 Medizin
Place:	Mainz
ROR:	https://ror.org/023b0x485
DOI:	http://doi.org/10.25358/openscience-8402
Version:	Published version
Publication type:	Zeitschriftenaufsatz
License:	CC BY
Information on rights of use:	https://creativecommons.org/licenses/by/4.0/
Journal:	Molecular psychiatry 27
Pages or article number:	5070 5085
Publisher:	Springer
Issue date:	2022
ISSN:	1476-5578
Publisher DOI:	10.1038/s41380-022-01804-3
Appears in collections:	DFG-491381577-H